Genetic testing: the key to quick and accurate diagnosis of primary immunodeficiencies

The contents of this article are informational only and are not intended to be a substitute for professional medical advice, diagnosis, or treatment recommendations. This editorial presents the views and experiences of the author and does not reflect the opinions or recommendations of the publisher of Rare Disease 360.

Genetic sequencing enables the early diagnosis and treatment of rare immune disorders. How can we improve its uptake across all medical specialties?

By Jolan Eszter Walter, MD, PhD

This is part 1 of a 2-part series authored by Dr. Walter. 

Just 10 or 15 years ago, genetic sequencing was available only to patients who were gravely ill, and after waiting several weeks for results, many of them decompensated or died. Even after news had been delivered, physicians could do little except help families understand an illness and its heritability.

Since then, the power of genetic testing has radically changed. Although the technology does not provide clear answers in every case, doctors now frequently use it to improve the outcomes of patients with rare, genetically based illnesses by expediting their diagnoses, which in turn enables swifter and more tailored treatment.

While uptake has been slow across many specialties, the time to embrace genetic testing has come, as the strategy may provide significant answers for our patients with rare primary immunodeficiencies (PIs).

One example is patients with activated PI3K delta syndrome (APDS), a progressive, underdiagnosed PI driven by heritable variants in the PIK3CD or PIK3R1 genes. With an average 7-year journey to diagnosis, these patients need earlier intervention to help avert symptoms that can include chronic respiratory infections and bronchiectasis; enlargement of the liver, spleen and/or lymph nodes; viruses such as Epstein-Barr; gastrointestinal (GI) disturbances; cytopenias; and blood cancers.^1-5

Genetic testing can help by definitively differentiating APDS from similar diseases, including autoimmune lymphoproliferative syndrome, autoimmune cytopenias, monogenic combined immunodeficiencies, common variable immune deficiency, and Evans syndrome—and it can do so more cost-effectively than upfront immunophenotyping.⁶

With these advantages in mind, it’s essential that we improve our uptake of genetic testing—not just in my own field of allergy and immunology, but across all medical specialties that might encounter these types of diseases.

Although many physicians haven’t had focused training in genetics since medical school, we’re all capable of implementing these tests. In this article, the first in a 2-part series, I’ll outline a 3-point action plan that can help the medical community incorporate genetic testing into practice.

1. Make Genetic Testing More Accessible

It’s simple for doctors to collect blood or saliva samples for sequencing, and they can order tests from commercial labs online.

But for our uptake to improve, genetic testing will need to become even more accessible and affordable.

In addition to the need to train staff to order tests and obtain patient consent, a current obstacle is that health insurance coverage for genetic sequencing is spotty and doesn’t always accommodate testing of at-risk relatives identified through detailed family genetic mapping. To reduce the financial burden for patients and their families, doctors or their staff can turn to programs that offer genetic testing for rare PIs at no cost, such as those run by nonprofit patient advocacy groups or sponsored by pharmaceutical companies.

Identifying an APDS variant within a family can ensure that the possibility of disease is considered from the family-planning stage and onward through a child’s life. Early genetic testing for members of affected families can prevent the disease from being overlooked, even if it initially presents with few symptoms and would otherwise be challenging for doctors to identify. Ultimately, this can help prevent organ damage, which frequently arises in these patients when diagnosis and therapy are delayed.

While some patients with immune-related symptoms must rely on insurance or pay out of pocket, genetic sequencing can still be the most cost-effective initial test for these rare disorders; in contrast, immunophenotyping can be much more expensive. For example, a genetic panel could cost hundreds of dollars, while a lymph node biopsy might cost thousands.

2. Train Doctors to Read Genetic Testing Reports

Many practicing physicians consider reading genetic test results to be prohibitively complicated, and until that changes, these assays will remain underutilized.

Variants are routinely reported as:

• Pathogenic
• Likely pathogenic
• Benign
• Likely benign
• Variants of uncertain significance (VUS)

To know which findings are actionable and explain the results to their patients, doctors need to understand the implications of each category. For instance, pathogenic or likely pathogenic results are associated with a proven disease-causing variant and warrant action in the clinic, whereas benign or likely benign results are considered medically inconsequential. VUS, meanwhile, have an unspecified meaning due to a lack of scientific evidence and require further investigation.

Embedding that understanding across medicine will require experts in genetic testing to partner with professional organizations and academic institutions to help educate their peers. The American Academy of Allergy, Asthma & Immunology and the Clinical Immunology Society are among the organizations that offer these kinds of educational sessions and resources.

Multidisciplinary participation and collaboration in these efforts is essential, as patients with lymphoproliferation are typically seen by numerous specialists beyond allergy/immunology. While individuals who see geneticists are likely to be quickly diagnosed, patients also may be treated by a broad range of other specialists, such as hematologists/oncologists, pulmonologists, and GI specialists. Those with APDS may also see psychiatrists or neurologists for cognitive delay.

It is crucial for doctors across all these specialties to feel comfortable ordering genetic tests and interpreting the results.

The effectiveness of this strategy has been demonstrated by the Houston Project, an initiative at Texas Children’s Hospital to identify the genetic causes of immune disorders. Researchers there have found that doctors shift treatment toward more effective options in 40% of cases following genetic testing.⁷

3. Increase Recognition of Immunodeficiencies

A widespread enthusiasm for employing genetic testing will represent a victory for both physicians and patients, but we won’t win that race until specialists of all kinds are clear on when to apply the technology.

A case in point is a family in which 3 members with lymphoproliferation were diagnosed with the same cancer. The initial patient had been diagnosed by a geneticist who saw the child due to a suspicious combination of developmental delay and alopecia. However, a physician missed the lymphoproliferation during initial examinations, instead testing for allergic rhinitis.

It can be easy to overlook the symptoms that characterize immune disorders because they so uncommonly present together in an actionable way. But it’s important for doctors to recognize, for instance, that a patient with lymph node enlargement and a history of recurrent infections is a prime candidate for genetic testing.

Fortunately, there are resources available to clarify these families of symptoms—for example, those available through organizations such as the Jeffrey Modell Foundation, the Immune Deficiency Foundation, and disease state-specific sites such as AllAboutAPDS.

With all that we know about the value of genetic testing in PIs and the resources available to support our use of this strategy, every allergist/immunologist should be gearing up to offer genetic testing in the clinic—as should the other specialists who so often collaborate in the diagnosis and treatment of our patients.

With that kind of cooperative effort, we can help ensure that rare and life-altering disorders of the immune system never go undiagnosed.

Jolan Eszter Walter, MD, PhD, is an international expert in primary immunodeficiencies and immune dysregulation who serves as division chief of the University of South Florida and Johns Hopkins All Children’s Pediatric Allergy & Immunology Programs. Her research is focused on better understanding diseases associated with the under- and overactive immune system and defining strategies for the early detection of susceptible individuals and novel approaches for precision treatment. This article was written for educational purposes, and the views expressed herein are solely those of the author. Editorial support was provided by a third party and paid for by Pharming Healthcare, Inc. No financial compensation or incentives were provided.

References

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